Longevity and lifespan have increased over the centuries thanks to improvements in medicine, nutrition, and the environment. Though these all are major contributors to a longer lifespan, another key factor is the regulation and expression of certain genetic factors and how they affect cellular function and proliferation, which vary from one individual to another. Damages to an organism's chromosomes throughout life are a major cause of aging and susceptibility to age related diseases such as cancers, Parkinson's disease, and Alzheimer's disease.
It has been shown that within a unique group of advanced age individuals, the centenarians who are people at or over the age of a hundred, a relatively slow increase in the frequency of some types of chromosomal aberrations are observed. Several studies confirm that these people have better efficiency of DNA repair or elimination of these unwanted cells (Bolognesi et al., Cancer Epidemiol. Biomark. Prev., 1997; 6:249-256; Wojda et al., Cancer Epidemiol. Biomark. Prev., 1997; 6:249-256; Zietkiewicz et al., Journal of Applied Genetics, 2009; 50(3):pp. 261-273).
The length of the telomere section of chromosomes, also called the “cap,” is related to longevity. As an organism ages the length of these “cap” regions shorten with every cellular division. This is particularly evident in peripheral blood leukocytes that have long telomeres at birth but by the second decade of life a drastically eroded and continue eroding throughout life at a slower pace (Calado, et al., PLoS One. 2009 Nov. 20; 4(11):e7926). As telomere caps shorten, the chromosomes become more prone to instability causing aneuploidy (an abnormal number of chromosomes), translocation (movement of chromosomal parts to a normative location in the genome), and mutations or deletions to genetic material (Calado, PLoS One. 2009 Nov. 20; 4(11):e7926). Gene instability and alterations in gene expression have been found to be hallmarks of eukaryotic aging (Oberdoerffer et al., Cell, 2008 Nov. 28; 135(5):907-18).
Unlike stem cells and some cancerous cells that have the ability to synthesize and use telomerase (a telomere lengthening enzyme), most somatic cells endure progressively shorter telomeres. Through senescence even adult stem cells that possess this ability are not able to overcome the inevitable loss contributing to human aging (Aubert, and Lansdorp, Physiol Rev. 2008 April; 88(2):557-79). Goto et al. identified that the effect of pro-inflammatory substances produced by the innate immune system may physiologically or pathologically contribute to aging. Pro-inflammatory signals once beneficial in the earlier stages of life may be harmful and antagonistically affect an individual in the later stages of life.
The aforementioned causes of aging can be attenuated by use of longevity prolonging substances such as resveratrol (3,5,4′-trihydroxy-trans-stilbene). These compounds act by simulating the expression of a particular category of enzymes, the sirtuins 1-7 or SIRTs, which are 299 to 555 amino acid long proteins. The SIRTs are a nicotinamide adenine dinucleotide (NAD+) dependent deacetylases that remove acetyl groups (—C2H3O+) from a variety of proteins, either activating or deactivating them by doing so.
Several SIRTs are localized to particular cellular compartments and tissue. Illustratively, SIRT2 is predominantly found expressed in the brain (Voelter-Mahlknecht et al., Int J. Oncol. 2005 November; 27(5):1187-96) and SIRT5 expression is predominately in the mitochondria of cardiac muscle cells (Mahlknecht et al., Cytogenet Genome Res. 2006; 112(3-4):208-12). While most of the SIRTs possess a life prolonging effect, currently the most studied is SIRT1.
Sirtuin-1 has many functional roles in the mammalian organism such as its ability to regulate metabolic function and gene expression. Aerobic capacity and mitochondrial oxidative phosphorylation have a great effect on longevity, neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's disease and are tightly linked to mitochondrial dysfunction. It has been shown that SIRT1 activation promotes proper mitochondrial function and energy and metabolic homeostasis by increasing PGC-1 activation, a key regulator of energy metabolism (Lagouge et al., Cell. 2006 Dec. 15; 127(6):1109-22; Liang et al., 2006; Rasouri et al., Med Sci (Paris). 2007 October; 23(10):840-4).
SIRT1 has been indicated in causing an autophagic effect in cells, autophagy is a process in which the cell recycles unnecessary cellular components through lysosomal degradation and reuses the material for new processes necessary to survival, which can help prolong an organism's life (Morselli et al., Autophagy. 2010 January; 6(1):186-8). The inhibition of enzymes such as PARP-1 (Poly[ADP-ribose] Polymerase 1), which can mediate cell death devoid of DNA damage may be crucial to longevity. SIRT1 is able to deacetylate and inactivate the active form of PARP-1, directly affecting its enzymatic activity. Also, SIRT1 can indirectly affect PARP activity by negatively regulating the promoter of PARP-1 gene (Rajamohan et al., Mol Cell Biol. 2009 August; 29(15):4116-29). SIRT-1 was also found to relocalize itself to damaged DNA to promote repair mechanisms, decreasing the amount of aberrations to chromosomes (Oberdoerffer et al., Cell, 2008 Nov. 28; 135(5):907-18).
Ablation of SIRT1 in murine liver tissue disrupted fatty acid oxidation and elevated cellular stress and pro-inflammatory cytokines, increasing cellular damage eventually leading to cell death. It is apparent that SIRT1 is necessary for proper liver function and can inhibit the over production of pro-inflammatory factors, possibly reducing the harmful effects they can have on an aging organism (Purushotham et al., Cell Metab. 2009 April; 9(4):327-38). A study by Alcendor et al. (Circ Res. 2007 May 25; 100(10):1512-21) using mice that over expressed SIRT1 in cardiac tissue demonstrates that moderate overexpression of SIRT1 can have a protective effect on the heart, attenuating oxidative stress and age-dependent increases in hypertrophy, apoptosis/fibrosis, mitochondrial dysfunction and also decreased the expression of senescent markers, i.e. INK4/ARF expression.
Another gene in the sirtuin family associated with increasing longevity is SIRT3. SIRT3 is typically localized in the mitochondria of cells but has also been found to be exported out of the mitochondria possibly for other functions or degradation. While in the mitochondrial SIRT3 plays a large role in cellular metabolism, it activates acetyl-CoA synthetase by deacetylation and also activates glutamate dehydrogenase and isocitrate dehydrogenase-2 by deacetylation, all of which are key regulators of metabolism (Allison et al., Cell Cycle. 2007 Nov. 1; 6(21):2669-77; Schlicker et al., J Mol. Biol. 2008 Oct. 10; 382(3):790-801). The overexpression on SIRT3 may also be linked to increased longevity. Illustratively, Sundaresan et al. (Mol Cell Biol. 2008 October; 28(20):6384-401) found SIRT3 overexpression to be stress responsive and protective of cardiac muscle cells from genotoxic and oxidative stress. The authors found this is accomplished by the sirtuin's ability to deacetylate the Ku70 protein. The deacetylated Ku70 protein can then associate itself with the proapoptotic protein Bax, making cells resistant to Bax-mediated cell death.
In model organisms such as mice and drosophila, underexpression of SIRTs appears to be detrimental to the organism's longevity (Bellizzi et al., Genomics. 2005 February; 85(2):258-63). The moderate overexpression of all the sirtuin genes can be beneficial for increasing longevity. Sirtuin-7 is typically expressed in the nucleus of cells and interacts with histones and RNA polymerase-1 (Ford et al., 2007). The overexpression of SIRT7 has been shown to increase the transcription of ribosomal DNA by RNA polymerase-1 increasing the amount of protein being translated and promoting proliferation. Depletion of SIRT7 stops proliferation, triggers apoptosis and greatly reduces RNA pol-1 activity signifying that SIRT7 is required for cell viability (Ford et al., 2007).
The mammalian sirtuins (SIRT1-SIRT7) are implicated in gene silencing, mitochondrial function, energy homeostasis, insulin sensitivity, and longevity (Yamamoto et al., Mol. Endocrinol, 2007; 21:1745-1755). Sirtuins (SIRTs) are longevity factors that appear to regulate critical cardio-protective pathways in the mammalian heart. Three family members, SIRT1, SIRT3, and SIRT7, block stress-induced cardiac hypertrophy (Schug et al., Aging (Albany N.Y.). 2010 Mar. 31; 2(3):129-32). SIRTs regulate metabolism and life span. Insulin resistance and subclinical atherosclerosis are associated with SIRT1 downregulation in monocytes. Glucotoxicity and lypotoxicity play a relevant role in quenching SIRT1 expression (de Kreutzenberg et al., Diabetes. 2010 April; 59(4):1006-15).
Type 2 diabetes is characterized by a combination of defective insulin secretion and insulin resistance that results from a progressive age-associated decline in β cell function. A recent study has reported that a reduction in SIRT1 activity with age contributes to this age-related impairment of β-cell function (Ramsey et al., Aging Cell. 2008 January; 7(1):78-88).
Longevity can be optimized by adoption of a healthy diet and life-style, including moderate exercise, a decrease in food intake together with a healthy diet, and elimination of smoking and other disease causing factors (Marques et al., Maturitas. 2010 February; 65(2):87-91). Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies.
Thus, there exists a need for compositions and methods of improving sirtuin expression or activity to promote improved longevity and decreased disease.